Low-dose diethystilbestrol in treatment of men with CRPC


It has been a long time since we saw any truly new data on the efficacy and safety of a very old form of hormonal therapy (diethylstilbestrol or DES) in the treatment of advanced prostate cancer. It is also important for patients diagnosed since about 1985 to be aware that, prior to the introduction of the LHRH agonists (leuprolide acetate, goserelin acetate, etc.) and the antiandrogens (flutamide, biacalutamide, etc.), DES was the standard “go to” drug used in the treatment of advanced prostate cancer — often at a dose of 3 or 5 mg/day.

For those who are interested, a review of the 80-year-long use of DES as a treatment for prostate cancer was published in the Scandinavian Journal of Urology in 2013 (by the same group of authors who conducted the retrospective data analysis discussed below).

A group of investigators in the UK has recently published a retrospective analysis of data from 194 men, all treated with DES at a dose of just 1 mg/day. These 194 men all had advanced prostate cancer that was “refractory to androgen suppression.” In other words, they had castration-resistant prostate cancer (CRPC).

Why were they treated with DES at just 1 mg/day as opposed to 3 or 5 mg/day? Because at the higher doses DES is known to come with a risk for serious cardiovascular side effects. However, a good deal of historic data has suggested that DES at 1 mg/day is effective and offers a far lower risk for cardiovascular side effects — particularly in men with no significant and established risk for cardiovascular disease.

At this point in time, we have seen only the abstract of this new paper by Turo et al. We are seeking to obtain a copy of the full text. In the interim, here is what is reported in the abstract:

    • The 194 patients were treated with DES between 1976 and 2010.
      • DES was given as second-line treatment in 58 patients.
      • DES was given as third- or fourth-line treatment in 136 patients.
    • At initiation of DES therapy the patients’ average (mean) PSA level was 96 ng/ml (range, 1.9 to 9,500 ng/ml).
    • Average (median) duration of DES treatment was 29 months.
    • PSA levels in response to DES therapy were
      • A decrease in PSA level of ≥ 50 percent in 95/194 patients (48.9 percent) (Group 1)
      • A decrease in PSA level of < 50 percent in 62/194 patients (31.9 percent) (Group 2)
      • No evident PSA response in 39/194 patients (19.1 percent) (Group 3)
    • Average (median) time to disease progression (i.e., an evident rise in PSA level) was
      • 250 days for men in Group 1
      • 150 days for men in Group 2
      • 90 days for men in Group 3
    • Average (median) overall survival from initiation of DES was
      • 576 days (range 482 to 690 days) for all men in the study
      • 756 days (range 670 to 1,429 days) for men in Group 1
      • 428 days (range 340 to 630 days) for men in Group 2
      • 329 days (range 287 to 510 days) for men in Group 3
    • 39/194 patients (20.1 percent) were still alive at the termination of the study.

There were no treatment-related deaths.

Turo et al. conclude that:

In the age of chemotherapy this study highlights the efficacy of estrogen therapy in castration-refractory prostate cancer. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.

In our opinion, this study appears to confirm that DES at a dose of 1 mg/day is an effective and safe form of treatment for men with CRPC. However, the real question is how it would compare to drugs like abiraterone acetate or enzalutamide in a randomized clinical trial. One way to establish this would be through an additional arm in the STAMPEDE trial in the UK. Another would be through a small pilot study somewhere in the USA or Europe.

DES is taken orally once a day (no injections and no patches to worry about). It is an old, cheap, and effective drug. It also appears to be safe if it is used at a dose of 1 mg/day and is not used in men with known risk for cardiovascular disorders. The “New” Prostate Cancer InfoLink has long believed that we missed a real opportunity to investigate the value of low-dose DES as a treatment for advanced prostate cancer in the mid 1980s and early 1990s, when such an opportunity had clearly been suggested by the data from studies conducted by the Veteran’s Administration Cooperative Urological Research Group (VACURG).

Can such a study be conducted now? We don’t know. What we do know is that it appears to be unethical to continue to use a placebo as a comparator in trials of any new drug for the treatment of CRPC. Maybe we should be using low-dose DES as the comparator instead!

4 Responses

  1. I’ve been using DES for the past 3 years: 2 mg/day for 2 months, then every other day for 1 month, then every fourth day for 1 month, and none for the next 8 months. PSA level goes to < 1 ng/ml within 60 days and the tumor disappears. I also take B12, aspirin, iron, folic acid and D3 concurrently with the DES to avoid the cardio problems. In the meanwhile I try homeopathic protocols, none of which has been helpful. DES is a lifesaver.

  2. There is such a Phase III trial in the UK. They recently extended the trial end date to 2021, and increased the sample size to 2,150 based on the success of the Phase II trials. The trial will randomly compare LHRH agonists to transdermal estrogen patches. It’s thought that the patch, which eliminates the serum peaks and valleys associated with pills, may be less hepatotoxic and have less associated clotting incidents.

  3. The trials that Allen cites are not using DES, but estradiol patches. This isn’t apparent in the articles about the trials, but is mentioned at the bottom of the “Phase II” article in the “Acknowledgements” section: “Merck Serono provided a discounted rate for FemSeven oestradiol patches.” Paul Abel has been the lead researcher for this trial and several British pilot trials using these patches. Abstracts for these trials can be found on PubMed.

    DES is a synthetic estrogen, while estradiol is a natural estrogen. One may have beneficial effects that the other has not, but this has not been fully understood. This is discussed in the “Discussion” section of an early report on progress with the Phase II trial:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564109

    A few years ago my own oncologist, Dr. Tomasz Beer of OHSU, conducted a few pilot studies of estradiol patches. He has told me that he is unable to acquire funding for further trials. (There would be no great profit in selling the patches, which are now available in generic form to treat female menopause.) He was also interested in developing a DES patch, but had similar funding problems. Also, he told me that an impediment regarding DES is that a lab test for concentrations of it in the serum has never been developed.

    I have been using estradiol patches for my hormone therapy for most of the last 9 years.

  4. Estrogens are a family of steroids. There’s another synthetic version called ethinyl estradiol, which is often given to women for oral estrogen replacement therapy because the liver doesn’t degrade it as quickly as estradiol. I only mention it because of a single case report I saw about a man in Japan who had become castrate-resistant with a rapidly climbing, double-digit PSA, but after taking the pills his PSA has been undetectable for 2 years so far.

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